1. Technical Field
The invention relates to an improved process for the preparation of macrocyclic compounds useful as agents for the treatment of hepatitis C viral (HCV) infections.
2. Background Information
The macrocyclic compounds of the following formula (I) and methods for their preparation are known from: Tsantrizos et al., U.S. Pat. No. 6,608,027 B1; Llinas Brunet et al, U.S. Application Publication No. 2003/0224977 A1; Llinas Brunet et al, U.S. Application Publication No. 2005/0075279 A1; Llinas Brunet et al, U.S. Application Publication No. 2005/0080005 A1; Brandenburg et al., U.S. Application Publication No. 2005/0049187 A1; and Samstag et al., U.S. Application Publication No. 2004/0248779 A1:
    wherein W is CH or N,    L0 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, hydroxy, or N(R23)2,    wherein each R23 is independently H, C1-6 alkyl or C3-6 cycloalkyl;    L1, L2 are each independently H, halogen, C1-4alkyl, —O—C1-4alkyl, or —S-C1-4alkyl (the sulfur being in any oxidized state); or    L0 and L1 or    L0 and L2 may be covalently bonded to form together with the two C-atoms to which they are linked a 4-, 5- or 6-membered carbocyclic ring wherein one or two (in the case of a 5- or 6-membered ring) —CH2— groups not being directly bonded to each other, may be replaced each independently by —O— or NRa wherein Ra is H or C1-4alkyl, and wherein said ring is optionally mono- or di-substituted with C1-4 alkyl;    R2 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, C1-6 thioalkyl , C1-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxy-C1-6alkyl, C6 or C10 aryl or Het, wherein Het is a five-, six-, or seven-membered saturated or unsaturated heterocycle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur;
said cycloalkyl, aryl or Het being substituted with R6,    wherein R6 is H, halo, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C3-6 cycloalkoxy, NO2, N(R7)2, NH—C(O)—R7; or NH—C(O)—NH—R7, wherein each R7 is independently: H, C1-6 alkyl or C3-6 cycloalkyl;    or R6 is NH—C(O)—OR8 wherein R8 is C1-6 alkyl or C3-6 cycloalkyl;    R3 is hydroxy, NH2, or a group of formula —NH—R9, wherein R9 is C6 or C10 aryl, heteroaryl, —C(O)—R10, —C(O)—NHR10 or —C(O)—OR10,            wherein R10 is C1-6 alkyl or C3-6 cycloalkyl;            D is a 5 to 10-atom unsaturated alkylene chain;    R4 is H, or from one to three substituents at any carbon atom of said chain D, said substituent independently selected from: C1-6 alkyl,    C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, and C1-6 thioalkyl; and    A is an amide of formula —C(O)—NH—R11, wherein R11 is selected from: C1-8 alkyl, C3-6 cycloalkyl, C6 or C10 aryl; C7-16 aralkyl and SO2R11A wherein R11A is C1-8 alkyl, C3-7 cycloalkyl or C1-6 alkyl-C3-7 cycloalkyl;    or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof;
The compounds of formula (I) are disclosed in the above-mentioned patent documents as being active agents for the treatment of hepatitis C virus (HCV) infections. The methods disclosed for the preparation of these compounds include many synthetic steps. The problem addressed by the present invention is to provide a practical and economical process which allows for the efficient manufacture of these compounds with a minimum number of steps and with sufficient overall yield.